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The novel orally active guanylhydrazone CPSI-2364 prevents postoperative ileus in mice independently of anti-inflammatory vagus nerve signaling

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Abstract

Purpose

Postoperative ileus (POI) is an iatrogenic complication of abdominal surgery, mediated by a severe inflammation of the muscularis externa (ME). Previously, we demonstrated that intravenous application of the tetravalent guanylhydrazone semapimod (CNI-1493) prevents POI, but the underlying mode of action could not definitively be confirmed. Herein, we investigated the effect of a novel orally active salt of semapimod (CPSI-2364) on POI in rodents and distinguished between its inhibitory peripheral and stimulatory central nervous effects on anti-inflammatory vagus nerve signaling.

Methods

Distribution of radiolabeled orally administered CPSI-2364 was analyzed by whole body autoradiography and liquid scintillation counting. POI was induced by intestinal manipulation with or without preoperative vagotomy. CPSI-2364 was administered preoperatively via gavage in a dose- and time-dependent manner. ME specimens were assessed for p38-MAP kinase activity by immunoblotting, neutrophil extravasation, and nitric oxide production. Furthermore, in vivo gastrointestinal (GIT) and colonic transit were measured.

Results

Autoradiography demonstrated a near-exclusive detection of CPSI-2364 within the gastrointestinal wall and contents. Preoperative CPSI-2364 application significantly reduced postoperative neutrophil counts, nitric oxide release, GIT deceleration, and delay of colonic transit time, while intraoperatively administered CPSI-2364 failed to improve POI. CPSI-2364 also prevents postoperative neutrophil increase and GIT deceleration in vagotomized mice.

Conclusions

Orally administered CPSI-2364 shows a near-exclusive dispersal in the gastrointestinal tract and effectively reduces POI independently of central vagus nerve stimulation. Its efficacy after single oral dosage affirms CPSI-2364 treatment as a promising strategy for prophylaxis of POI.

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Abbreviations

ME:

Muscularis externa

KHB:

Krebs–Henseleit buffer

GIT:

Gastrointestinal transit

POI:

Postoperative ileus

PMN:

Polymorphonuclear neutrophils

p38-MAPK:

p38 Mitogen-activated protein kinase

NO:

Nitric oxide

IM:

Intestinal manipulation

icv:

Intracerebroventricular

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Acknowledgments

We greatly appreciate Cytokine PharmaSciences, Inc. (King of Prussia, PA, USA) for providing CPSI-2364. This study was supported by grants from the Deutsche Forschungsgemeinschaft (KA1270/3-1/2) and BONFOR (O-112.0040 and O-112.0043).

Conflicts of interest

Thais Sielecki was an employee of Cytokine PharmaSciences, Inc., King of Prussia, PA, USA and an inventor on several patents and applications relating to CPSI-2364 that are owned by Cytokine PharmaSciences, Inc. Sven Wehner and Joerg Kalff are inventors on an international PCT application related to CPSI-2364 that is owned by Cytokine PharmaSciences, Inc. and the University of Bonn, Germany. All other authors have nothing to declare. The authors state that they have full control of all primary data and that they agree to allow the journal to review the data if requested.

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Authors and Affiliations

  1. Department of Surgery, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    S. Wehner, T. O. Vilz, N. Sommer, G. S. Hong, M. Lysson, B. Stoffels, D. Pantelis & J. C. Kalff

  2. Cytokine PharmaSciences, Inc., King of Prussia, PA, USA

    T. Sielecki

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  1. S. Wehner
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  2. T. O. Vilz
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  3. N. Sommer
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  4. T. Sielecki
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  5. G. S. Hong
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  6. M. Lysson
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  7. B. Stoffels
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  9. J. C. Kalff
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Correspondence to J. C. Kalff.

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S. Wehner and T. O. Vilz contributed equally to this work.

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Wehner, S., Vilz, T.O., Sommer, N. et al. The novel orally active guanylhydrazone CPSI-2364 prevents postoperative ileus in mice independently of anti-inflammatory vagus nerve signaling. Langenbecks Arch Surg 397, 1139–1147 (2012). https://doi.org/10.1007/s00423-012-0989-6

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